The small molecule, ibudilast, (3-isobutyryl-2-isopropylpyrazolo[1,5-a]pyridine), is a non-selective inhibitor of cyclic nucleotide phosphodiesterase (PDE) (Fujimoto et al., (1999) J. of Neuroimmunology 95:35-92). Ibudilast displays glial attenuating properties, differentiating it from some other PDE inhibitors (Suzumuar et al., Brian Res. (1999) 837:203-212). Glial cell activation may have multiple, diverse neurological consequences including contributions to neuropathic pain, opiate withdrawal/addiction and Alzheimer's (Narita et al., Nihon Shinkei Seishin Yakurigaku Zasshi (2006) 26:33-39). Ibudilast also acts as an LTD4 antagonist, an anti-inflammatory, a PAF antagonist, and a vasodilatatory agent (Thompson Current Drug Reports). Ibudilast is thought to exert a neuroprotective role in the central nervous system of mammals, presumably via suppression of the activation of glial cells (Mizuno et al., (2004) Neuropharmacology 46: 404-411).
Ibudilast has been widely used in Japan for relieving symptoms associated with ischemic stroke or bronchial asthma. Marketed indications for ibudilast in Japan include its use as a vasodilator, for treating allergy, eye tissue regeneration, ocular disease, and treatment of allergic ophthalmic disease (Thompson Current Drug Reports). In recent clinical trials, its use in the treatment of multiple sclerosis, an inflammatory disease of the central nervous system, has been explored (News. Medical. Net; Pharmaceutical News, 2 Aug. 2005).
The cytokine macrophage migration inhibitory factor (MIF) has been shown to play a role in multiple inflammatory processes, primarily by influencing macrophage function (Bloom and Bennett, Science (1966) 153:80; and Calandra and Roger, Nat. Rev. Immunol. (2003) 3:791-800). Neutralizing antibodies to MIF have been demonstrated to be effective therapeutics in preclinical models of rheumatoid arthritis, endotoxemia and septic shock (Calandra et al., Nat. Med. (2000) 6:164-170; and Santos and Morand, Wein. Med. Wochenschr. (2000) 156:11-18). MIF mRNA is upregulated in microglia three days post-spinal cord injury and may act as a modulator to inflammatory cytokines (Koda et al., Acta Neuropathol. (2004) 108:31-36).
While the use of ibudilast for a number of varying indications, including the regulation of mononuclear and glial cell response (Kawanokuchi et al., Neuropharmacology (2004) 46:734-742; Feng et al., Mult. Scler. (2004) 10:494-498) has been reported to date, to the best of applicants' knowledge, its activity as an inhibitor of the cytokine macrophage migration inhibitory factor (MIF) has heretofore remained unexplored.
There remains a need for identifying improved compounds and compositions that inhibit MIF.